Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tribbles Homolog 1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101899

Synonyms

 C8FW;  Skip1;  Trb1;

Historical Background

Trib1 is the member of tribbles family pseudokinases with Trib2 and Trib3 in mammals and is a homolog of Drosophila tribbles (Yokoyama and Nakamura 2011). Tribbles was first discovered as a regulator of string/cdc25 in morphogenesis (Grosshans and Wieschaus 2000). At same time, Mata et al. showed that tribbles induced degradation of string via the proteasome pathway (Mata et al. 2000). As a result of studies by these two groups, overexpression of tribbles was found to suppress cell cycle at G2 by proteasome-mediated degradation of string. Soon after discovery of tribbles in Drosophila, slbo/C/EBP was found to be regulated by tribbles also via proteasome pathway (Rorth et al. 2000). Mammalian homologs of tribbles consist of three closely related genes, Trib1/C8FW/SKIP1, Trib2/C5FW/SKIP2/SINK, and Trib3/NIPK/SKIP3 (Wilkin et al. 1997; Mayumi-Matsuda et al. 1999; Tang et al. 2000).

Structure of TRIB1 Pseudokinase

Both human and mouse TRIB1 genes encode 372aa proteins containing a pseudokinase domain at the middle like TRIB2 and TRIB3 (Fig. 1). The pseudokinase domain of TRIB1 consists of 12 subdomains that belong to the protein kinase superfamily (Hanks and Hunter 1995). Conserved amino acid sequences that are required for core kinase structure are mostly conserved. However, several consensus sequences for protein phosphorylation are missing in TRIB1. The complete lack of GXGX2GXV in subdomain I, the loss of histidine and asparagine in HRDLKX2N in VIB, and the lack of the DFG triplet in VII are important variations (Fig. 1) that are responsible for loss of kinase activity in Trib1.
Tribbles Homolog 1, Fig. 1

The structure of tribbles proteins. (a) Tribbles consists of N-terminal, pseudokinase and C-terminal domains. The number of amino acids for each domain in Drosophila and mammals are indicated. (b) Amino acid sequences of the pseudokinase domain in human and murine tribbles. The conserved amino acid sequences that are characteristic to the kinase superfamily are indicated in red. (c) Three unique motifs: catalytic loop, MEK1 binding motif and COP1 binding motif. Adapted from Yokoyama and Nakamura (2011)

A putative nuclear localization signal, [K/R]2X2[D/E]X[D/E], is located within the N-terminus (Hegedus et al. 2007). There are two functionally important motifs in the C-terminal region. A hexapeptide motif [A/D]QVVPD that was identified in TRIB3 as an E3 ubiquitin ligase COP1-binding site is also present in TRIB1 as DQIVPE (Qi et al. 2006). The COP1-binding motif is important for tribbles’ core function for degradation of the C/EBP family proteins. Another important motif in the C-terminus is an MEK-binding site (Yokoyama et al. 2010). The details of these two important motifs are discussed in the next section.

Trib1 Acts as an Adaptor Protein

Drosophila tribbles downregulates string and slbo at the protein level. C/EBPα, a mammalian homolog of slbo, is degraded by Trib1 and Trib2 in a proteasome-dependent manner (Keeshan et al. 2006; Dedhia et al. 2010). Conversely, the increase of C/EBPβ protein was detected in Trib1 knockout mice (Yamamoto et al. 2007). Posttranscriptional suppression of C/EBP proteins is important for myeloid cell differentiation, myeloid leukemogenesis, and adipocyte differentiation (Keeshan et al. 2006; Dedhia et al. 2010; Yokoyama et al. 2010; Naiki et al. 2007).

By binding with MEK1, Trib1 induces enhanced and extended phosphorylation of ERK1/ERK2 and thereby protects leukemia cells from apoptosis induced by cytokine depletion (Jin et al. 2007; Yokoyama et al. 2010). The critical role of the MEK1-binding motif of Trib1 was further exhibited that abrogation of Trib1 leukemogenic activity by deletion or point mutants of the motif (Yokoyama et al. 2010). Interestingly, interaction between Trib1 and MEK1 enhances C/EBPα degradation by Trib1, indicating that Trib1 functions as an adaptor protein (Fig. 2). The molecular mechanisms of MAPK activation or suppression by Trib1 remains unclear. Trib1 overexpression inhibits MEKK1-induced stress kinase signaling, and Trib1 blocks AP-1 activation downstream of JNK in smooth muscle cells via interaction with MKK4 (Kiss-Toth et al. 2006; Sung et al. 2007). Cell context-dependent activation of MAPK signaling by Trib1 is proposed, and affinity between Trib1 and different MAPKKs might be important (Kiss-Toth et al. 2006; Sung et al. 2006). To explain the mechanism, a competition model between tribbles proteins and MAPKKs has been reported (Guan et al. 2016).
Tribbles Homolog 1, Fig. 2

The role of Trib1 in leukemogenesis. Trib1 functions as an adaptor between the MEK/ERK pathway and C/EBPa. Trib1 interacts with MEK1 and enhances phosphorylation of ERK1/2, which promotes cell proliferation and suppresses apoptosis (1). In addition, Trib1 recruits COP1 to C/EBPa (2) and ERK phosphorylation is required for promotion of C/EBPa ubiquitination (3). C/EBPa is also downregulated by hnRNP E2, which requires ERK phosphorylation (4). Proteasome-mediated degradation and post-transcriptional suppression of C/EBPa results in inhibition of myeloid differentiation (5). Adapted from Yokoyama and Nakamura (2011)

References

  1. Dedhia PH, Keeshan K, Uljon S, Xu L, Vega ME, Shestova O, et al. Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia. Blood. 2010;116(8):1321–8.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Grosshans J, Wieschaus E. A genetic link between morphogenesis and cell division during formation of the ventral furrow in Drosophila. Cell. 2000;101(5):523–31.PubMedCrossRefGoogle Scholar
  3. Guan H, Shuaib A, De Leon DD, Angyal A, Salazar M, Velasco G, et al. Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways. Sci Report. 2016;6:32667.CrossRefGoogle Scholar
  4. Hanks SK, Hunter T. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 1995;9(8):576–96.PubMedCrossRefGoogle Scholar
  5. Hegedus Z, Czibula A, Kiss-toth E. Tribbles: a family of kinase-like proteins with potent signaling regulatory function. Cell Signal. 2007;19(2):238–50.PubMedCrossRefGoogle Scholar
  6. Jin G, Yamazaki Y, Takuwa M, Takahara T, Kaneko K, Kuwata T, et al. Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood. 2007;109(9):3998–4005.PubMedCrossRefGoogle Scholar
  7. Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez CG, et al. Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell. 2006;10(5):401–11.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Kiss-Toth E, Wyllie DH, Holland K, Marsden L, Jozsa V, Oxley KM, et al. Functional mapping and identification of novel regulators for the Toll/Interleukin-1 signalling network by transcription expression cloning. Cell Signal. 2006;18(2):202–14.PubMedCrossRefGoogle Scholar
  9. Mata J, Curado S, Ephrussi A, Rorrth P. Tribbles coordinates proliferation and morphogenesis in Drosophila by regulating String/CDC25 proteolysis. Cell. 2000;101(5):511–22.PubMedCrossRefGoogle Scholar
  10. Mayumi-Matsuda K, Kojima S, Suzuki H, Sakata T. Identification of a novel kinase-like gene induced during neuronal cell death. Biochem Biophys Res Commun. 1999;258(2):260–4.PubMedCrossRefGoogle Scholar
  11. Naiki T, Saijou E, Miyaoka Y, Sekine K, Miyajima A. TRB2, a mouse tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBPβ. J Biol Chem. 2007;282(33):24075–82.PubMedCrossRefGoogle Scholar
  12. Qi L, Heredia JE, Altarejoz JY, Screaton R, Goebel N, Niessen S, et al. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science. 2006;312(5781):1763–6.PubMedCrossRefGoogle Scholar
  13. Rorth P, Szabo K, Texido G. The level of C/EBP protein is critical for cell migration during Drosophila oogenesis and is tightly controlled by regulated degradation. Mol Cell. 2000;6(1):23–30.PubMedCrossRefGoogle Scholar
  14. Sung HY, Francis SE, Crossman DC, Kiss-Toth E. Regulation of expression and signaling modulator function of mammalian tribbles is cell-type specific. Immunol Lett. 2006;104(1–2):171–7.PubMedCrossRefGoogle Scholar
  15. Sung HY, Guan H, Czibula A, King AR, Eder K, Heath E, et al. Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways. J Biol Chem. 2007;282(25):10379–87.CrossRefGoogle Scholar
  16. Tang K, Finley RL, Nie D, Honn KV. Identification of 12-lipoxygenase interaction with cellular protein by yeast two-hybrid screening. Biochemistry. 2000;39(12):3185–91.PubMedCrossRefGoogle Scholar
  17. Wilkin F, Suarez-Huerta N, Robaye B, Peetermans J, Liebert F, Dumont JE, et al. Characterization of a phosphoprotein whose mRNA is regulated by the mitogenic pathways in dog thyroid cells. Eur J Biochemist. 1997;248(3):660–8.CrossRefGoogle Scholar
  18. Yamamoto M, Uematsu S, Okamoto T, Matsuura Y, Sato S, Kumar H, et al. Enhanced TLR-mediated NF-IL6 dependent gene expression by Trib1 deficiency. J Exp Med. 2007;204(9):2233–9.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Yokoyama T, Nakamura T. Tribbles in disease: signaling pathways important for cellular function and neoplastic transformation. Cancer Sci. 2011;102(6):1115–22.PubMedCrossRefGoogle Scholar
  20. Yokoyama T, Kanno Y, Yamazaki Y, Takahara T, Miyata S, Nakamura T. Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis. Blood. 2010;116(15):2768–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Carcinogenesis, The Cancer InstituteJapanese Foundation for Cancer ResearchTokyoJapan